Medtronic (NYSE:MDT) revealed the details of a clinical trial of its Symplicity renal denervation treatment for hypertension, but said it still plans to investigate the treatment even though the study showed only meager improvements in high blood pressure compared with a sham procedure.
In a widely anticipated presentation of data from Medtronic’s Symplicity HTN-3 trial in Washington Saturday at the American College of Cardiology’s annual meeting, 1 of the study’s lead investigators said the renal denervation arm showed only a 2.39mm Hg reduction in systolic blood pressure after 6 months. Ambulatory systolic pressure, measured over 24 hours, was down 1.96mm Hg for the Symplicity arm. There were no significant differences in safety between the study’s 2 groups, Dr. Deepak Bhatt said.
Bhatt said physicians using the treatment where it’s approved overseas should carefully consider renal denervation for hypertension in light of the results.
"As far as clinical practice outside the U.S., I think doctors need to look at these data and honestly ask themselves, is their clinical practice so dissimilar from the patients in our trial that they would not believe a rigorously done, randomized clinical trial?" he said. "Personally, I would be cautious about offering the procedure to patients in the face of a large, randomized clinical trial."
Data on the 535 patients treated in the study, also published today in the New England Journal of Medicine, showed that the mean reduction in systolic pressure after 6 months was 14.13mm Hg for the RDN-treated arm and 11.74mm Hg for the sham arm.
Medtronic said it still plans to pursue renal denervation for resistant hypertension, backed by recommendations from an independent panel of experts.
"Based on the unique nature of these findings and support from the independent panel that additional research be considered to better understand the effects of the Symplicity technology for renal denervation, we remain convinced that resistant hypertension is a large unmet medical need and renal denervation remains a promising opportunity," Medtronic’s renal denervation general manager Nina Goodheart said in prepared remarks.
Medtronic said the panel approved its plans to shut down its Symplicity HTN-4 trial, which it suspended along with trials in India and Japan in January. The company will consult with those countries about whether to re-start the HTN-Japan and HTN-India studies, according to the release. The Symplicity RDN treatment for hypertension will still be offered in jurisdictions where it’s approved and Medtronic will continue to enroll patients in a global registry, the company said.
"Medtronic will continue to provide access to the Symplicity system in countries where it has regulatory approval and will continue to support a global hypertension clinical program," according to the release. "Based on our detailed analysis of Symplicity HTN-3, we believe further clinical investigation is warranted; Medtronic will determine the optimal path forward, along with FDA, for the next U.S. [investigational device exemption]."
And Medtronic will "continue to pursue its studies in other disease states, including atrial fibrillation, chronic kidney disease, heart failure, etc.," according to the release.
Medtronic’s chief medical officer, Dr. Rick Kuntz, said the company is evaluating "many factors that may have contributed to the observed efficacy results beyond the employment of a more rigorous trial design."
"There are several differences between the Symplicity studies, including the populations studied, required medication dosing, patient behaviors in terms of lifestyle and drug adherence, and potential for procedural variability. We are evaluating the contributions of these potential factors, which are hypothesis-generating and will guide us in determining the path forward with FDA," Kuntz said in a statement.
Other companies respond carefully
Medtronic’s announcement of Symplicity HTN-3’s efficacy failure in January shocked medtech, prompting suspension of enrollment in other Symplicity trials around the world and sparking other major players to suspend their hypertension RDN programs or even abandon the field altogether. For its part, Medtronic has said that a writedown of its renal denervation assets is likely.
How the Symplicity HTN-3 data will affect other companies invested in renal denervation technology is not yet clear. Rival RDN players Boston Scientific (NYSE:BSX) and St. Jude Medical (NYSE:STJ) in January declared that they’re not willing to dump their development efforts just yet, speculating that the technology used in Medtronic’s trial is substantially different from either Boston Scientific’s Vessix or St. Jude’s Enlightn.
In a statement to the media following the news at ACC, President of Peripheral Interventions at Boston Scientific Jeff Mirviss said: "We believe that the Boston Scientific Vessix System is a highly differentiated technology supported by compelling clinical evidence and a strong clinical program. We will carefully examine the data from this study and work collaboratively with the scientific community to determine the next steps for our Vessix clinical program."
Previously, fearing that Medtronic’s Symplicity device would already be on the market, St. Jude had called off the Enlightn IV trial of the next generation of its renal denervation technology in December, just a few months after it began, over concerns that it would be tough to enroll patients in a trial in which they could end up in the sham arm when another device with similar technology was already on the market. The trial of St. Jude’s multi-electrode Enlightn device was slated to enroll about 590 patients between the ages of 18 and 80 with high blood pressure that isn’t well-managed with drugs.
An unnamed co-principal investigator in Medtronic’s Symplicity HTN-3 trial in January said the results may signal the end of the technology because the efficacy failure was based on renal denervation as an approach to treat hypertension, rather than on the device.
Experts provide insight into where to go from here
Dr. Darrel Francis, an early skeptic of the high reductions in systolic pressure in early RDN studies who later defended the technique, told MassDevice.com yesterday that it’s time to refresh the slate when it comes to RDN and hypertension.
"Symplicity 3 teaches us that the history of denervation needs to be wiped, and started afresh, relying only on randomized blinded data. At least now the unknown unknowns are becoming known unknowns," Francis told us. "It is a huge relief that at last there is a trial reported that has the design features that have for the last 2 decades been known to be essential for trials of intervention for hypertension: Randomization and blinding.
"Denervation should be studied as an option for patients who have reached the end of their willingness to increase medical therapy," he added. "I would recommend such patients enter a randomized, blinded trial of denervation. The science of denervation is young, having been truly born only today with the results of Symplicity-3."
Dr. Michael Jaff, chairman of the Mass. General Hospital Institute for Heart, Vascular and Stroke Care and the medical director of the vascular core lab for Symplicity HTN-3, also said the trial marked a new path for the field of renal denervation.
"This is a well-designed and well-run trial, with more questions now about where this field must go from here. I suspect issues about objective markers of effective denervation will help, as would optimal patient selection," Jaff told us.
It’s possible that medication compliance or effectiveness during the trial could have affected the results, if blood pressure medications were working better in some patients rather than others, or, if some patients failed to take all their meds as prescribed, he added.
"Compliance and use of various antihypertensive agents, including aldosterone antagonists, may have played a role in the trial results," Jaff said. "The only time I would consider referral for denervation is if I were truly convinced that I could not control the blood pressure and if I absolutely excluded any secondary cause for refractory hypertension."